The lung is an organ dedicated to gas exchange. Gas exchange occurs at the septal surface of the approximately 300 million alveoli in the adult human lung. These myriads of units provide a large diffusion area (50-100 square meters for a human lung) where gas exchange occurs between the air entering the alveoli and the blood contained in capillaries wrapped around the alveoli.
Classic concepts of the mechanics and functioning of the lung at the level of alveoli and alveolar ducts have relied on inferences largely drawn from three different sources. These sources are:
1) Determining airway pressure and volume ventilation to obtain mechanical structure-function information on the whole lung, which in turn reflects on the properties of the lung's connective tissue and the mean properties of the air-liquid surfaces; PA1 2) In vitro analyses of biopsies taken from a small number of regions of the lung to determine the presence of infection or tumor tissue; and PA1 3) Visual methods including computer aided tomography and X-rays which may be used to identify gross morphological changes in vivo such as blockages, lumps and inflammation but are not suited for fine resolution imaging because of interference caused by the gas-liquid interfaces in the lungs. PA1 4) Morphometric analysis of lung tissue fixed and sectioned for microscopy. PA1 5) Gas exchange analyses of gross and large regional differences by multiple inert gas exchange, positron emission tomography and single photon emission tomography.
None of these methods provide direct means for measuring the dynamic properties of large numbers of small regions within the lungs of a living animal in real time.
Recent advances have brought about the recognition that the relevant structural geometry (Fung,(1975), Stress, deformation, and atelectasis of the lung, Circ. Res. 37:481-496; Karakaplan et al., (1980), A mathematical model of lung parenchyma, J. Biomech. Eng. 102:124-136; Mead et al.,(1970) Stress distribution in lungs: a model of pulmonary elasticity, J. Appl. Physiol. 28:596-608; Wilson,(1981) Relations among recoil pressure, surface area, and surface tension in the lung, J. Appl. Physiol. 50:921-926) of the lung is highly complex. Stereological techniques have been used on fixed tissues for measuring the effects on the alveolar surface configuration of changes in lung volume (Forrest, (1970), The effect of changes in lung volume on the size and shape of alveoli, J. Physiol. London 210:533-547; Gil et al., Morphological study of pressure-volume hysteresis in rat lungs fixed by vascular perfusion, Respir. Physiol. 15:190-213 (1972); Gil et al., Alveolar volume-surface area relation in air-and saline-filled lungs fixed by vascular perfusion, J. Appl. Physiol. 47:990-1001 (1979); Klingele et al., (1970), Alveolar shape changes with volume in isolated, air-filled lobes of cat lung, J. Appl. Physiol. 28:411-414) and of changes in the state of the air-liquid interface (Bachofen et al., (1979), Alterations of mechanical properties and morphology in excised rabbit lungs rinsed with a detergent, J. Appl. Physiol. 47:1002-1010; Gil et al. 1972 (cited above)). However, there are limitations inherent in using fixed tissues. These include: restriction to analysis of static circumstances; difficulties in being certain that no changes occur during the various processes which assail tissue between the original physiological condition and its fixed dehydrated sliced and stained state; and the necessity of studying a specimen from a different lobe or animal to obtain each individual physiological datum.
There is therefore a substantial need for new methods of studying the spatial distribution of changes that are too small to be otherwise detectable and yet are important to gas exchange. Such techniques would provide much needed information on the functioning of healthy lung tissue, as well as information on what constitutes abnormal performance of lung tissue that might be associated with a chronic pulmonary pathological condition.
Emphysema is an example of a chronic obstructive pulmonary disease. It is a debilitating disease affecting 1.65 million Americans, half of whom are over age 65, at an annual cost of over $4 billion. The estimated number of patients has increased over 40% since 1982 and chronic obstructive pulmonary disease (COPD) is the fourth-ranking cause of death in the United States (American Lung Association Lung Disease Data, Publication of American Lung Association, 1994). The lung damage is irreversible and current therapy is usually limited, at best, to symptomatic relief. Lung transplantation is being increasingly used for treatment of emphysema, but it is very expensive and limited by the small number of donor lungs available. More recently, lung reduction surgery, especially in elderly patients with severe emphysema, has gained increasing popularity with chest physicians and surgeons.
The distribution of emphysematous lesions can vary widely, and delineating the boundaries between more versus less affected regions is difficult in situ. Compounding the problem is that the bullous lesions that are detectable with current technology are very large in comparison with intrinsic alveolar size and that septal destruction that decreases the normal surface area, by, e.g., a factor of two, is virtually invisible to current measurement techniques. A method is needed to delineate boundaries between healthy and impaired tissues during surgery to maximise the effectiveness of surgical intervention.